Interleukin 2 (IL-2) plays a critical role in the regulation of proliferation and differentiation of hematopoietic cells (27, 29). IL-2 exerts its multiple biological activities through its binding to a specific cell surface receptor (IL-2R) (30), including protein tyrosine kinase (PTK) activation, and nuclear proto-oncogene expression which may be critical for cellular proliferation (16, 29). IL-2R contains at least three distinct subunits; the .alpha.-chain, the .beta.-chain and the .gamma.-chain (5, 9, 28). Among these subunits, both the IL-2R .beta.- and .gamma.-chains belong to a newly identified superfamily of cytokine receptors, characterized by four conserved cysteines and the sequence Trp-Ser-X-Trp-Ser (the "WS motif SEQ ID NO: 18") in their extracellular domains (1, 2). Notably, none of the IL-2R subunits possesses any known catalytic activity such as PTK activity.
The expression of different combinations of the IL-2R subunits gives rise to various forms of IL-2R, each of which exhibiting different binding affinity to IL-2 (28). The "high-affinity" IL-2R (Kd; 10.sup.-11) consists of the heterotrimer .alpha.-, .beta.- and .gamma.-chains, the "intermediate-affinity" IL-2R (Kd; 10.sup.-9) results from the heterodimer .beta.- and .gamma.-chains, whereas the "low-affinity" IL-2R (Kd; 10.sup.-8) can be generated by expression of the .alpha.-chain alone. IL-2R .beta.-chain possesses the largest cytoplasmic domain, consisting of 288 amino acids (a.a.) and was shown to play a critical role in IL-2 signal transduction (8). When the human IL-2R .beta.-chain cDNA was introduced into murine IL-3-dependent pro-B cell line BAF-B03, which normally expresses the endogenous IL-2R .alpha.- and .gamma.-chains, but not the .beta.-chain, these cells were capable of proliferating in response to IL-2 (3, 8). Further expression studies with deletion mutant cDNAs of the IL-2R .beta.-chain revealed that a restricted cytoplasmic region of the IL-2R .beta.-chain, designated the "serine-rich" region (S-region), is indispensable for c-myc gene induction and for mitogenesis following IL-2 stimulation of the BAF-B03 cells (26). Another cytoplasmic region of the IL-2R .beta.-chain, rich in acidic amino acids, designated the "acidic" region (A-region), is required in addition to the S-region for the src-family PTK activation and p21.sup.iras activation and for c-foslc-jun gene induction following IL-2 stimulation of BAF-B03 cells (6, 7, 17, 24, 26). Several lines of evidence suggest that the IL-2R .gamma.-chain may also be critical for IL-2-induced signal transduction (29). Moreover, IL-2R .gamma.-chain is suggested to be a shared common component among the IL-2, IL-4 and IL-7 receptors and possibly other cytokine receptors (14, 15, 21, 23). Mutations of IL-2R .gamma.-chain have been found in X-linked severe combined immunodeficiency patients who show defects in T-cell development (22), providing evidence for the critical role of IL-2R .gamma.-chain in cytokine signaling. Furthermore, recent studies have indicated that the functional cooperation between the cytoplasmic domains of IL-2R .beta.-chain and .gamma.-chain is critical for IL-2 signaling (11, 19, 20).
Because of the importance of IL-2R-mediated processes for normal body functions and disease, there is a need of better understanding of these processes as well as the need of new tools for influencing them.